Evaluation of Treprostinil Palmitil Inhalation Powder on Pulmonary Vascular Resistance in Pulmonary Arterial Hypertension: A Phase 2b Randomized, Double-Blind, Placebo-Controlled Study
- Trial ID
- 2023-505541-99-00
- Protocol
- INS1009-202
- Sponsor
- Insmed Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the effect of **Treprostinil Palmitil Inhalation Powder (TPIP)** compared with placebo on **Pulmonary Vascular Resistance (PVR)** in participants with **Pulmonary Arterial Hypertension**. This is clinically relevant as reducing PVR is crucial in managing the disease, potentially improving hemodynamics and patient outcomes.
Secondary objectives include:
- To assess the effect of TPIP compared with placebo on exercise capacity.
- To assess the safety and tolerability of TPIP compared with placebo.
- To evaluate the pharmacokinetics (PK) of TP and TRE in plasma.
- To evaluate the effect of TPIP compared with placebo on the concentration of NT-proBNP in blood.
Participants
The clinical trial involves a total of **76 participants** diagnosed with **Pulmonary Arterial Hypertension** (PAH). The study population includes both male and female subjects, aged between 18 and 75 years. Participants were selected based on specific criteria, including a stable health status with a diagnosis of WHO Group 1 PAH for at least three months and classified as New York Heart Association (NYHA)/WHO functional class II or III. The trial includes individuals who are on stable pulmonary hypertension (PH) therapy, consisting of up to two medications from specified classes, with no changes in medication or dosage for at least 30 days prior to screening. Participants are required to have a body mass index (BMI) within the range of 18.0-37.0 kg/m² and must demonstrate the ability to perform a six-minute walk test (6MWT) with a distance between 150 and 450 meters. The trial population is characterized by a documented pre-bronchodilator predicted FEV1 ≥70% and FEV1/FVC ratio ≥70% within one year of screening. Both male and female participants are required to adhere to contraceptive guidelines consistent with local regulations to prevent pregnancy during the study. The trial includes a vulnerable population, ensuring that all participants are capable of providing informed consent and complying with protocol requirements.
Plans and Procedures
The clinical trial is a **Phase 2b**, randomized, double-blind, multicenter, placebo-controlled study designed to evaluate the efficacy, safety, and pharmacokinetics of **Treprostinil Palmitil Inhalation Powder** in participants with **Pulmonary Arterial Hypertension** (PAH). The primary objective is to assess the effect of Treprostinil Palmitil Inhalation Powder (TPIP) compared with placebo on Pulmonary Vascular Resistance (PVR). The trial is expected to last approximately 16 weeks, with participant involvement beginning from the screening visit and continuing through the end-of-study visit.
Participants will undergo a sequence of study visits, starting with an inclusion (screening) visit to confirm eligibility based on criteria such as age, 6-minute walk test (6MWT) distance, and hemodynamic findings from right heart catheterization. Following successful screening, participants will be randomized to receive either the investigational product or placebo. The trial includes follow-up visits at Weeks 5, 10, and 16 to monitor changes from baseline in PVR, 6MWT distance, and other secondary endpoints such as plasma pharmacokinetic parameters and NT-proBNP concentration. The end-of-study visit will conclude the participant's involvement, assessing overall safety and efficacy outcomes.
The expected length of participant involvement is approximately 16 weeks, with conditions for early termination including significant adverse events or non-compliance with study protocols. Participants must adhere to stable pulmonary hypertension therapy and contraceptive requirements throughout the study. The trial aims to provide comprehensive data on the therapeutic potential of Treprostinil Palmitil Inhalation Powder in managing PAH, contributing to the understanding of its impact on pulmonary vascular resistance and overall patient health.
Treatment
The clinical trial involves the administration of **Treprostinil Palmitil Inhalation Powder**, an experimental medication designed for the treatment of **Pulmonary Arterial Hypertension**. This medication is provided in the form of an inhalation powder, with the active substance being **Treprostinil Palmitil**, a chemical compound. The pharmaceutical form is specifically designed for **inhalation use**. The maximum daily dose is 640 micrograms, with a total maximum dose of 71.68 milligrams over a treatment period of 16 weeks. The administration is facilitated by a Plastiape capsule-based dry powder inhaler device (RS01 Mod 7), which is CE marked and ensures precise delivery of the medication. The inhalation powder is not a pediatric formulation and is manufactured by INSMED INC.
In addition to the experimental treatment, a **placebo** is utilized in the study. The placebo consists of inhalation powder capsules that mimic the experimental treatment but do not contain the active substance. These capsules are available in three dosage strengths corresponding to the experimental treatment: 80 micrograms, 160 micrograms, or 320 micrograms. The placebo is used to maintain the double-blind nature of the study, ensuring that neither the participants nor the investigators are aware of the treatment assignments. This allows for an unbiased assessment of the efficacy and safety of the experimental medication.
Efficacy
The efficacy of **Treprostinil Palmitil Inhalation Powder** in the treatment of Pulmonary Arterial Hypertension (PAH) will be assessed through a series of predefined endpoints. The primary endpoint is the change from baseline in Pulmonary Vascular Resistance (PVR) at Week 16. Secondary endpoints include changes from baseline in the 6-Minute Walk Test (6MWT) distance at Weeks 5, 10, and 16, as well as the percent change in 6MWT distance at these same timepoints. Additionally, the frequency of adverse events and changes from baseline in clinical laboratory evaluations, vital signs, ECG, and physical examination over the 16-week treatment period will be monitored. Plasma pharmacokinetic parameters of Treprostinil Palmitil, including Cmax, tmax, AUC24, AUC∞, AUClast, CL/F, Vd/F, and t½, will be measured on Day 1 and at Week 10. The change from baseline in the concentration of NT-proBNP at Weeks 5, 10, and 16 will also be evaluated.
These efficacy parameters will be collected and analyzed at specified intervals throughout the study duration. The assessments will be conducted using validated scales and laboratory tests to ensure accuracy and reliability. The study is designed to provide comprehensive data on the efficacy of the investigational product compared to placebo, with the aim of improving treatment outcomes for patients with PAH.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participants must be ≥ 18 to ≤ 75 years at the time of signing the ICF
- Participants must have a diagnosis of WHO Group 1 PH (PAH) in any of the following subtypes: • idiopathic; • heritable or • drug/toxininduced or CTD-associated PAH • Congenital heart disease-related with simple systemic-to-pulmonary shunt at least 1 year following repair
- PAH diagnosis for at least 3 months.
- New York Heart Association (NYHA)/WHO functional class II or III
- Medical history, physical examination, vital signs, ECG, and clinical laboratory results consistent with their degree of PAH and treatment.
- Participants must be on stable PH therapy consisting of up to 2 medications from the following classes: • Endothelin receptor antagonists (eg, ambrisentan, bosentan, macitentan) • Phosphodiesterase type 5 inhibitors (eg, sildenafil, tadalafil) • Guanylate cyclase stimulator (eg, riociguat)"
- No change in PH medications (eg, ambrisentan, bosentan, macitentan, sildenafil, tadalafil, riociguat) or dosage for at least 30 days prior to Screening.
- No change in long-term diuretic use dosage for at least 30 days prior to Screening (single or rescue doses allowed, per the Investigator).
- Documented pre-bronchodilator predicted FEV1 ≥70% and FEV1/FVC ratio ≥ 70% within 1 year of Screening. If documented spirometry is not available, pulmonary function testing will be performed during Screening.
- At least two 6MWTs during Screening with a 6MWT distance between 150 and 450 meters in length where both values are within 15% of each other.
- Right heart catheterization at Screening (or within 30 days prior to Screening, if available) with all the following hemodynamic findings: • Mean PAP ? 25 mmHg at rest • PCWP ? 15 mmHg • PVR of ? 5 WU"
- BMI within the range 18.0-37.0 kg/m2 (inclusive).
- Male and female participants must use contraceptives that are consistent with local regulations regarding the methods of contraception for those participating in clinical studies. • Male participants: Male participants who are not sterile and have female partners of childbearing potential, must be using effective contraception from Day 1 to at least 90 days after the last dose of study drug. Such methods include true abstinence (refraining from heterosexual intercourse during the study), combined (estrogen and progestogen containing) or progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine devices, intrauterine hormone-releasing systems. • Female participants: Women must be postmenopausal (defined as no menses for 12 months without an alternative medical cause), surgically sterile, (ie, hysterectomy and/or bilateral salpingo-oopherectomy), or using highly effective contraception methods (ie, methods that alone or in combination achieve <1% unintended pregnancy rates per year when used consistently and correctly) from Day 1 to at least 90 days after the last dose of study drug. Such methods include true abstinence (refraining from heterosexual intercourse during the study), combined (estrogen and progestogen containing) or progestogen-only hormonal contraception associated with inhibition of ovulation and supplemented with a double barrier (preferably male condom), intrauterine devices, intrauterine hormone-releasing systems, or vasectomized partner. For WOCBBP ≤45 years, an additional confirmatory testing of FSH level with a threshold of >40 mIU/mL should be performed to be considered infertile. All WOCBP must have a negative urine pregnancy test prior to randomization."
- Female participants of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine pregnancy test at Baseline.
- Male participants with pregnant or non-pregnant WOCBP partner must use a condom in order to avoid potential exposure to embryo/fetus.
- Capable of giving signed informed consent
- Able to understand and comply with protocol requirements
Exclusion Criteria
- History of PH other than idiopathic, hereditary, drug/toxin-induced, repaired simple congenital heart disease, or CTD-associated PAH (eg, complex congenital heart disease-associated PAH, portal hypertensionassociated PAH, PH belonging to Groups 2 through 5).
- Allergy, or documented hypersensitivity or contraindication, to TPIP or TRE or mannitol (an excipient of the TPIP formulation).
- Per the Investigator's discretion, previous intolerance to prostacyclin analogues or receptor agonists or previous chronic use (>30 days) of a prostacyclin analogue or receptor agonist within 30 days of the Screening Visit.
- QTcF interval > 480 ms on resting ECG at Screening, not including participants with right bundle branch block (RBBB) leading to a prolongation of the QRS.
- Any known ventricular or supraventricular tachyarrhythmia except for paroxysmal atrial fibrillation and any symptomatic bradycardia.
- History of heart disease including left ventricular ejection fraction (LVEF) ? 40% or clinically significant valvular, constrictive, or symptomatic atherosclerotic heart disease.
- Systolic BP < 90 mm Hg at Screening
- Participation in a cardio-pulmonary rehabilitation program within 30 days of Screening Visit.
- Evidence of thromboembolic disease as assessed by VQ scan, pulmonary angiography, or pulmonary CT scan.
- Acutely decompensated heart failure within 30 days of Screening Visit.
- Abnormal renal function (estimated glomerular filtration rate < 30 mL/min/1.73m2) at Screening.
- Active liver disease or hepatic dysfunction manifested as: in • Elevated liver function test results (ALT or AST > 2 × ULN) • Bilirubin > 1.5 × ULN (isolated bilirubin > 1.5 × ULN; ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%) • Known hepatic or biliary abnormalities, not including Gilbert's syndrome or asymptomatic gallstones"
- History of HIV infection
- Established diagnosis of hepatitis B viral infection, or positive for HBsAg at the time of Screening. • Participants who have gained immunity for hepatitis B virus infection after vaccination are eligible for the study. • Participants with positive HBcAbs are eligible for the study only if the hepatitis B virus DNA level is undetectable."
- Established diagnosis of hepatitis C viral infection at the time of screening. Participants positive for hepatitis C antibody are eligible for the study only if hepatitis C virus RNA is negative.
- Active and current symptomatic COVID-19 or previous severe disease and/or hospitalization due to COVID-19
- Use of live attenuated vaccines within 30 Days of the Screening Visit.
- Participants with Down's Syndrome.
- History of abnormal bleeding or bruising with a platelet count of <100,000/?L at Screening.
- History of organ transplantation.
- Known or suspected immunodeficiency disorder
- Severe concomitant illness(es) that, in the Investigator's judgment, would adversely affect the participant's participation in the study.
- Any clinically significant abnormal laboratory values at Screening or diseases or disorders (eg, cardiovascular, pulmonary, gastrointestinal, liver, kidney, neurological, musculoskeletal, endocrine, metabolic, psychiatric, physical impairment) that, in the opinion of the Investigator, may put the participant at risk by participating in the study, or interfere with the participant's treatment, assessment, or influence the results of the study, or have compliance issues with the study or have a planned or anticipated major surgical procedure during the study.
- History of alcohol or drug abuse within 6 months prior to Screening.
- Any other medical or psychological condition including relevant laboratory abnormalities at Screening that, in the opinion of the Investigator, suggest a new and/or insufficiently understood disease.
- Acute or chronic impairment (other than dyspnea), limiting the ability to comply with study requirements, in particular with 6MWT.
- Participants with current or recent (past 30 days) lower respiratory tract infection
- History of malignancy in the past 5 years, with exception of completely treated in situ carcinoma of the cervix and completely treated non-metastatic squamous or basal cell carcinoma of the skin.
- Change in PH medication (endothelin receptor agonists, phosphodiesterase type 5 inhibitors, and guanylate cyclase stimulators or diuretics) between Screening and Baseline.
- Use of any investigational drug/device or participation in any investigational study within 30 days prior to the screening
- Current use of cigarettes (as defined by CDC) or e-cigarettes: An adult who has smoked at least 100 cigarettes in his or her lifetime, and who currently smokes either every day or somedays.
- Participants who currently inhale marijuana (recreational or medical).
- Pregnant or breastfeeding.
- Absolute neutrophil count ? 1000/?L at Screening.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 22 Dec 2021 | 2 |
 Belgium | Not Recruiting | 22 Dec 2021 | 3 |
 Denmark | Not Recruiting | 22 Dec 2021 | 1 |
 Germany | Not Recruiting | 22 Dec 2021 | 6 |
 Italy | Not Recruiting | 22 Dec 2021 | 5 |
 Spain | Not Recruiting | 22 Dec 2021 | 6 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
TREPROSTINIL PALMITIL INHALATION POWDER | Test | INHALATION POWDER | INHALATION USE | 640 | 16 | PRD11347437 |
Placebo (inhalation powder capsules) containing 1 of 3 dosage strengths of TPIP80 μg, 160 μg, or 320 μg | Placebo | N/A | — | — | — | N/A |
TREPROSTINIL PALMITIL INHALATION POWDER | Test | INHALATION POWDER | INHALATION USE | 640 | 16 | PRD11347438 |
TREPROSTINIL PALMITIL INHALATION POWDER | Test | INHALATION POWDER | INHALATION USE | 640 | 16 | PRD11347439 |